Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

Sungyong You, Seung Ah Yoo, Susanna Choi, Ji Young Kim, Su Jung Park, Jong Dae Ji, Tae Hwan Kim, Ki Jo Kim, Chul Soo Cho, Daehee Hwang, Wan Uk Kim

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

Original languageEnglish
Pages (from-to)550-555
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
Publication statusPublished - 2014 Jan 16

Fingerprint

Systems Analysis
Rheumatoid Arthritis
Fibroblasts
Macrophages
Interleukin-1
Synoviocytes
Basic Helix-Loop-Helix Transcription Factors
Synovitis
Gene Expression Profiling
Myeloid Cells
Osteoblasts
Transcriptome
Osteoarthritis
Cartilage

ASJC Scopus subject areas

  • General

Cite this

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach. / You, Sungyong; Yoo, Seung Ah; Choi, Susanna; Kim, Ji Young; Park, Su Jung; Ji, Jong Dae; Kim, Tae Hwan; Kim, Ki Jo; Cho, Chul Soo; Hwang, Daehee; Kim, Wan Uk.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 1, 16.01.2014, p. 550-555.

Research output: Contribution to journalArticle

You, Sungyong ; Yoo, Seung Ah ; Choi, Susanna ; Kim, Ji Young ; Park, Su Jung ; Ji, Jong Dae ; Kim, Tae Hwan ; Kim, Ki Jo ; Cho, Chul Soo ; Hwang, Daehee ; Kim, Wan Uk. / Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 1. pp. 550-555.
@article{51e6790aa15a4903875f4733c10f540c,
title = "Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach",
abstract = "Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.",
author = "Sungyong You and Yoo, {Seung Ah} and Susanna Choi and Kim, {Ji Young} and Park, {Su Jung} and Ji, {Jong Dae} and Kim, {Tae Hwan} and Kim, {Ki Jo} and Cho, {Chul Soo} and Daehee Hwang and Kim, {Wan Uk}",
year = "2014",
month = "1",
day = "16",
doi = "10.1073/pnas.1311239111",
language = "English",
volume = "111",
pages = "550--555",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "1",

}

TY - JOUR

T1 - Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

AU - You, Sungyong

AU - Yoo, Seung Ah

AU - Choi, Susanna

AU - Kim, Ji Young

AU - Park, Su Jung

AU - Ji, Jong Dae

AU - Kim, Tae Hwan

AU - Kim, Ki Jo

AU - Cho, Chul Soo

AU - Hwang, Daehee

AU - Kim, Wan Uk

PY - 2014/1/16

Y1 - 2014/1/16

N2 - Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

AB - Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

UR - http://www.scopus.com/inward/record.url?scp=84891949499&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891949499&partnerID=8YFLogxK

U2 - 10.1073/pnas.1311239111

DO - 10.1073/pnas.1311239111

M3 - Article

C2 - 24374632

AN - SCOPUS:84891949499

VL - 111

SP - 550

EP - 555

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 1

ER -